RESUMEN
Purpose: Familial exudative vitreoretinopathy (FEVR) is an inherited retinal disease in which the retinal vasculature is affected. Patients with FEVR typically lack or have abnormal vasculature in the peripheral retina, the outcome of which can range from mild visual impairment to complete blindness. A missense mutation (p.His455Tyr) in ZNF408 was identified in an autosomal dominant FEVR family. Little, however, is known about the molecular role of ZNF408 and how its defect leads to the clinical features of FEVR. Methods: Using CRISPR/Cas9 technology, two homozygous mutant zebrafish models with truncated znf408 were generated, as well as one heterozygous and one homozygous missense znf408 model in which the human p.His455Tyr mutation is mimicked. Results: Intriguingly, all three znf408-mutant zebrafish strains demonstrated progressive retinal vascular pathology, initially characterized by a deficient hyaloid vessel development at 5 days postfertilization (dpf) leading to vascular insufficiency in the retina. The generation of stable mutant lines allowed long-term follow up studies, which showed ectopic retinal vascular hyper-sprouting at 90 dpf and extensive vascular leakage at 180 dpf. Conclusions: Together, our data demonstrate an important role for znf408 in the development and maintenance of the vascular system within the retina.
Asunto(s)
Proteínas de Unión al ADN/fisiología , Vitreorretinopatías Exudativas Familiares , Vasos Retinianos/patología , Animales , Proteínas de Unión al ADN/genética , Vitreorretinopatías Exudativas Familiares/genética , Vitreorretinopatías Exudativas Familiares/fisiopatología , Mutación Missense , Pez CebraRESUMEN
The young male alpaca ear and the back skins were used to investigate the effect of transforming growth factor receptor-ß I (TGFßR I) on alpaca hair follicles and hair growth. The expression level and location of TGFßR I in alpaca ear and dorsal skin were detected through real-time quantitative PCR (RT-PCR) and paraffin section immunohistochemical technique (ICC-P). The results shown TGFßR I was lower expression in back skin compared to ear skin and the mean density of the positive reaction in ear skin was significantly higher than back skin. The targeted relationship with let-7b was detected using the dual-luciferase reporter vector of TGFßR I, which showed a significant target relationship between let-7b and TGFßR I. After transfection with let-7b eukaryotic expression vector, the relative mRNA expression of TGFßR I in alpaca skin fibroblasts did not differ, while the relative protein level was significantly decreased. In summary, a higher TGFßR I expression level in the ear skin suggests that TGFßR I may inhibit coat hair elongation. Further studies showed TGFßR I protein was downregulated by let-7b through transcriptional repression.